ArticleNature2011
Single-molecule fluorescence reveals sequence-specific misfolding in multidomain proteins.
Article in Nature, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers.
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Who cites it
98 citing papers in PubMed.
- Residue-Level Energetic Analysis of Transient Misfolding in the Whirlin PDZ Tandem Reveals a Possible Connection to an AlphaFold-Predicted Alternative Topology.International journal of molecular sciences · 2026Article
- Dimerization of natively folded molecules drives misfolding and aggregation in Cys-depleted variants of cataract-associated human lens γD-crystallin.The Journal of biological chemistry · 2026Article
- Coupled Binding and Folding of NS2B/NS3 Protease and Linker Effects Revealed by Topology-Based Modeling.The journal of physical chemistry. B · 2026Article
- Dimerization of natively folded molecules drives misfolding and aggregation in Cys-depleted variants of cataract-associated human lens γD-crystallin.bioRxiv : the preprint server for biology · 2026Article
- Coupled Binding and Folding of NS2B/NS3 Protease and Linker Effects Revealed by Topology-based Modeling.bioRxiv : the preprint server for biology · 2026Article
- Dissecting the Structural Features of Folding Asymmetry and Transient Misfolding in a Multidomain PDZ Scaffold.Small science · 2026Article
- Adjacent domains drive the emergence of misfolded intermediates in the folding pathway of the PDZ4 from MAGI1.BBA advances · 2026Article
- Full-Length Context Disrupts Folding of IgG-Binding Domains of Protein A.bioRxiv : the preprint server for biology · 2025Article
- The human ribosome modulates multidomain protein biogenesis by delaying cotranslational domain docking.Nature structural & molecular biology · 2025Article
- Functions of Intrinsically Disordered Regions.Biology · 2025Review
- GRB2: A dynamic adaptor protein orchestrating cellular signaling in health and disease.Biochemistry and biophysics reports · 2024Review
- Article
- Mechanisms and pathology of protein misfolding and aggregation.Nature reviews. Molecular cell biology · 2023Review
- The long and the short of Periscope Proteins.Biochemical Society transactions · 2022Review
- Multi-layer sequential network analysis improves protein 3D structural classification.Proteins · 2022Article
- On the Effects of Disordered Tails, Supertertiary Structure and Quinary Interactions on the Folding and Function of Protein Domains.Biomolecules · 2022Review
- Co-Translational Folding of Multi-Domain Proteins.Frontiers in molecular biosciences · 2022Review
- Interactions between nascent proteins and the ribosome surface inhibit co-translational folding.Nature chemistry · 2021Article
- Single-molecule optical tweezers reveals folding steps of the domain swapping mechanism of a protein.Biophysical journal · 2021Article
- The Proteome Folding Problem and Cellular Proteostasis.Journal of molecular biology · 2021Review
38 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors.
Funding
Abstract
A large range of debilitating medical conditions is linked to protein misfolding, which may compete with productive folding particularly in proteins containing multiple domains. Seventy-five per cent of the eukaryotic proteome consists of multidomain proteins, yet it is not understood how interdomain misfolding is avoided. It has been proposed that maintaining low sequence identity between covalently linked domains is a mechanism to avoid misfolding. Here we use single-molecule Förster resonance energy transfer to detect and quantify rare misfolding events in tandem immunoglobulin domains from the I band of titin under native conditions. About 5.5 per cent of molecules with identical domains misfold during refolding in vitro and form an unexpectedly stable state with an unfolding half-time of several days. Tandem arrays of immunoglobulin-like domains in humans show significantly lower sequence identity between neighbouring domains than between non-adjacent domains. In particular, the sequence identity of neighbouring domains has been found to be preferentially below 40 per cent. We observe no misfolding for a tandem of naturally neighbouring domains with low sequence identity (24 per cent), whereas misfolding occurs between domains that are 42 per cent identical. Coarse-grained molecular simulations predict the formation of domain-swapped structures that are in excellent agreement with the observed transfer efficiency of the misfolded species. We infer that the interactions underlying misfolding are very specific and result in a sequence-specific domain-swapping mechanism. Diversifying the sequence between neighbouring domains seems to be a successful evolutionary strategy to avoid misfolding in multidomain proteins.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.